The research portfolio was determined by a literature search uncovering relevant research texts published from 2001 through June 2020, including peer-reviewed articles funded by the WTCHP and other entities. Records were included if they were in English and addressed the 9/11 attacks, populations, or pertinent health conditions, care, or outcomes. Synthesis was grouped by broad categories of aerodigestive disorders (
Section 3.3.1), adult mental health (
Section 3.3.2), cancer (
Section 3.3.3), vulnerable populations (
Section 3.3.4) and emerging conditions (
Section 3.3.5). Articles not classifiable were binned as “other”.
As of 30 June 2020, there were 944 publications eligible for synthesis. Of these, 291 (31%) were funded under the WTCHP. The total literature is nearly equally separated into publications on responders and non-responders (i.e., WTCHP survivors and Registry community members), with several studies including both populations. In contrast, most WTCHP-funded publications (78%) examined responders. In total, about three in four publications examined health burden and etiology, whereas the remainder characterized exposures or interventions (e.g., clinical, health services, and policy research). Among focus areas, most articles (34%) addressed adult mental health conditions, followed by vulnerable populations (19%), aerodigestive disorders (18%), emerging conditions (18%) and cancer (3%). Restricting articles to WTCHP-funded research, the order shifts to aerodigestive disorders (29%), mental health (26%), emerging conditions (23%), vulnerable populations (12%), and cancer (7%) (
Figure 2).
A broad overview of the research is described below. More weight was given to positive findings in efforts to portray the potential health burden.
3.3.1. Aerodigestive Disorders
Approximately 28% of the research dollars competitively awarded was attributed to aerodigestive disorders, which encompassed an array of conditions or diseases of the airway (pharynx and larynx), pulmonary tract (trachea, bronchi, and lungs), and upper digestive tract (esophagus). Aerodigestive disorders comprise the largest WTCHP certification category, accounting for 56% of members with certifications submitted through March 2020. Chronic rhinosinusitis, gastroesophageal reflux disorder (GERD), asthma, sleep apnea, chronic respiratory disorder (from fumes/vapors), and WTC-exacerbated chronic obstructive pulmonary disease are among the top aerodigestive disorders. There is considerable comorbidity within these outcomes, and there is growing evidence linking aerodigestive disorders and posttraumatic stress disorder (PTSD) [
9,
10,
11,
12,
13,
14,
15]. Those presenting with multiple conditions generally require more complex treatments and experience poorer outcomes and reduced health-related quality of life [
9,
13,
16].
Significant respiratory effects were apparent immediately following the attacks. Within the first 48 h, 90% of rescue workers (
n = 10,116) reported an acute cough that was regularly accompanied by nasal congestion, chest tightness, or chest burning. Within 6 months, 333 of these responders had a continued WTC-related cough (also known as “World Trade Center cough”) that required four or more consecutive weeks of medical leave. Of these, 173 remained either on medical leave or light duty or were pending a disability retirement evaluation nearly a year later [
17]. Spirometry, taken before and after the attacks revealed significant declines in lung function in exposed firefighters shortly following the attacks [
18]. This analysis also revealed that persons with predominantly upper-airway symptoms were more likely to return to work compared to those with predominantly lower-airway symptoms. This same study found associations between exposure intensity (measured as time of arrival onsite) and airway hyperreactivity and incidence of World Trade Center cough. Among those presenting with World Trade Center cough, over 80% also reported upper-airway symptoms, such as nasal congestion, nasal drip, and sore throat, and nearly 90% reported symptoms of GERD [
18].
Overall, studies found higher aerodigestive disorder prevalence among responders than that in the general population and highest in those with greatest exposure [
19]. Temporal trends in symptom prevalence have varied, with prevalence of dyspnea, wheeze, rhinosinusitis, and GERD remaining relatively stable over years post 9/11, whereas cough and sore throat have declined steeply within the first 4 years [
19,
20]. A substantial health burden remains. In a longitudinal study of rescue/recovery workers (
n = 27,449), the 9-year cumulative incidence was 27.6%, 42.3%, 39.3% for asthma, sinusitis and GERD, respectively [
14]. In 2016, the prevalence of age-adjusted asthma and GERD diagnosed after 9/11 in Registry enrollees (
n = 36,897) was 14.3% and 20.7%, respectively [
16]. Similarly, several studies of FDNY responders have shown persistent bronchial hyperreactivity and accelerated declines in lung function in some subjects nearing two decades post-exposure [
21,
22,
23,
24].
Similar dose-dependent patterns of lower and upper airway symptoms were observed in the survivor population [
25,
26]. Within the first year following the attacks, increased respiratory symptoms (predominately a cough, with dyspnea and wheezing to a lesser degree) were observed among residents near the WTC site compared to residents in an unexposed control area. Although they were resolved over time in many exposed residents, symptoms persisted in significant numbers [
16,
26]. Reasons for response heterogeneity remain elusive, although a recent study of survivors suggested that peripheral airway dysfunction and PTSD may contribute to the persistence of lower respiratory symptoms [
27].
3.3.2. Mental Health Conditions
A wide variety of mental health disorders fall under the broad category of mental health conditions described in the Zadroga Act, such as PTSD, major and atypical depressive disorders, panic disorder, and various anxiety disorders. Research in this area has been vast, comprising over a fifth (USD 26 M) of the WTCHP research dollars spent. About 22% of certified conditions were for mental health disorders.
Much of the available research centers on PTSD, a particularly disabling response to traumatic exposure with substantial comorbidity. Extensive literature, beginning immediately following 9/11, has been reviewed in several publications [
28,
29,
30,
31,
32]. In general, studies suggest a relatively large and persistent exposure-dependent burden of 9/11-related PTSD among the affected population. Injury, loss of loved ones, and witnessed horror are among the strongest predictors [
31]. Prevalence rates are heterogeneous across studies, varying widely by study design, time, population, and exposure type (e.g., physical vs. psychosocial). As examples, PTSD prevalence rates within eight weeks of the attacks ranged from 8% to 23% in studies of highly exposed first responders [
30] and 8–11% in residents. [
33,
34]. Less than one-third of studies are longitudinal; however, there is evidence of declining PTSD prevalence over time except for rescue/recovery workers, who appear to have lower prevalence in the first 3 years that increases thereafter [
28]. A meta-analysis of 10 studies indicated that responders (e.g., police, firefighters, rescue/recovery workers and volunteers) had lower PTSD risk (odds ratio, OR = 1.61, 95% CI: 1.39, 1.87) compared to civilians (OR = 2.71, 95% CI: 2.35, 3.12) [
31]. There were seven experimental or quasi-experimental studies examining PTSD treatments, mostly among residents (
n = 6), including studies of children (
n = 2) [
35,
36,
37,
38,
39,
40,
41,
42]. Treatments, randomization, and study methodologies varied; however, findings generally supported exposure-based intervention therapies to reduce fear-based symptoms [
28].
There are fewer studies examining major depressive disorder (MDD) in WTC populations. MDD is among the most common illnesses worldwide, contributing over 8% to the global years lived with disability [
43]. Although MDD etiology is unclear, there is mounting evidence of increased MDD prevalence from environmental stressors such as mass disasters [
44,
45,
46,
47]. A study of the New York metropolitan area residents found a prevalence of 9.4% within 6 months of the WTC attack compared to an expected six-month period prevalence of MDD in unexposed populations of 1.5% to 2.8% [
48]. A similar study restricted the sample to Manhattan residents living south of Canal Street (within approximately one mile of the WTC site) found 16.8% with depression-like symptoms [
34]. Other surveillance reported symptoms of major depression in 12% of NYC transit workers stationed near the site [
49], and 16% of clean up and recovery workers [
50]. Although longitudinal data are mostly lacking for this population, there is evidence suggesting many experienced an increase MDD prevalence within six months of the attack, with a subsequent decline to normal baseline rates thereafter [
48]. Nevertheless, subgroups exist who are persistently affected or present with recurring symptomatology years after the event [
51,
52]. This response heterogeneity is consistent with findings from a recent review of 54 studies of trajectories following potential trauma, which suggested four general trajectories, namely (in order by frequency) resilience, recovery, chronic stress, and delayed onset [
53].
A recent longitudinal study examining mortality patterns in Registry enrollees compared to the general population found increased deaths from suicide among rescue/recovery workers (SMR = 1.82, 95% CI: 1.35, 2.39), but not community members (SMR = 0.86, 95% CI: 0.53, 1.31) [
54]. This is the first and only study reporting increased suicide in a WTC subpopulation. Additional research is needed to clarify this association. Future research should include other investigations aimed to characterize resilience in the affected population, such as studies examining the relationship between mental illness and intentional self-medication.
3.3.3. Cancer
Cancer accounts for about 13% of WTCHP certified conditions. Non-melanoma skin cancer occurred most often, comprising about 27% of certified cancers, followed by prostate cancer at 21%. Consequentially, cancer research accounts for a large portion (21%) of the funds awarded. There are descriptive and analytic studies examining cancer mortality and incidence, with a few studies examining mechanisms or treatment [
54,
55,
56,
57,
58,
59,
60,
61,
62,
63,
64,
65,
66,
67,
68,
69,
70,
71,
72,
73,
74,
75,
76]. There are also notable reviews [
77,
78]. Most information stems from a set of longitudinal studies examining cancer incidence in FDNY responders [
55,
56], rescue/recovery workers [
57,
58], and Registry registrants [
59,
60], which are the focus of this discussion.
The FDNY study examined cancer patterns in 9853 male firefighters, 8927 of whom were exposed to 9/11 hazardous agents as WTC responders [
55]. Follow-up was until 2008. Overall cancer risks were not increased in adjusted analyses compared to the general population (standardized incidence ratio, SIR = 1.02 (95% CI: 0.90, 1.15); however, significantly elevated risk was observed for thyroid cancer (SIR = 2.17, 95% CI: 1.23, 3.82). There was some evidence on modestly increased malignant melanoma, non-Hodgkin lymphoma, and prostate cancer. SIRs were generally increased among exposed firefighters compared to those unexposed. An update was conducted comparing 11,457 FDNY firefighters who were WTC responders to an external control group of 8220 firefighters employed in Chicago, Philadelphia, and San Francisco with follow-up until 2009 [
56]. Thyroid cancer remained elevated (relative risk, RR = 3.43, 95% CI: 0.94, 18.94). Prostate cancer was elevated during the latter half of follow-up (2005–2009; RR = 1.38, 95% CI: 1.01, 1.88).
Shapiro et al. (2019) recently updated cancer incidence in 28,729 rescue/recovery workers [
58]. Follow-up was through 2013. Cases were identified through linkage with six state tumor registries. Exposure indices were derived from self-reported information on arrival time, exposure to the dust cloud, ever/never working on the debris pile, and cumulative days worked on WTC efforts. Expected numbers of cancer cases were calculated based on state rates and national rates. Exposure-response was examined using multivariable Cox proportional hazards regression for all cancer sites combined and for prostate cancer. SIRs were elevated for all cancer sites combined (SIR = 1.09, 95% CI: 1.02, 1.16), prostate cancer (SIR = 1.25, 95% CI: 1.11, 1.40), thyroid cancer (SIR = 2.19, 95% CI: 1.71, 2.75), and leukemia (SIR = 1.41, 95%: CI: 1.01, 1.92). Regression models did not yield evidence of an exposure–response association for either outcome examined.
The most recent update on cancer incidence in the Registry cohort included 35,476 community members and 24,863 responders followed through 2011 [
60]. Cancers were identified by linkage to 11 state cancer registries; expected numbers of cancers were based on New York State rates. Separate analyses were conducted for responders and community members. Qualitative descriptions of WTC exposures were used to classify exposure as high, intermediate, or low. Prostate cancer and skin melanoma were significantly elevated in both populations (responders: SIR = 1.43, 95% CI: 1.25, 1.63 and SIR = 1.49, 95% CI: 1.05, 2.06, respectively; community members: SIR = 1.27, 95% CI: 1.10, 1.46 and SIR = 1.54, 95% CI: 1.12, 2.07) compared to the general population. Thyroid cancer was significantly elevated only in responders while breast cancer and non-Hodgkin lymphoma were significantly elevated only among community members. Internal analyses showed a significant exposure-response for bladder cancer and log-transformed cumulative exposure scores (HR at unit log-score = 2.18, 95% CI: 1.10, 4.34,
p = 0.03), but not for any other exposure metric. This finding merits cautious interpretation because log-transformation of the exposure can result in overestimating the response in the low-dose range [
79]. A significant exposure-response trend was observed for skin melanoma in community members across ordinal categories of exposure (HR = 1.53, 95% CI: 1.04, 2.23).
Based on these observations, other studies have examined cancers of a priori interest. For example, there is emerging evidence of increased prevalence of monoclonal gammopathy of undetermined significance (MGUS) among WTC-exposed firefighters. MGUS, a nonmalignant outcome, can progress to multiple myeloma in some cases [
72]. Another study indicated WTC-dusts are highly capable of inducing
mdig (mineral dust-induced gene, also known as mina53, MINA, or NO52) in normal B cells and malignant myeloma cell lines. The levels of mdig mRNA and protein are associated with multiple myeloma progression and prognosis [
74]. Still, the current evidence of increased multiple myeloma in WTC populations is inconsistent. Modestly increased risk was observed in studies of firefighters (SIR = 1.49, 95% CI: 0.56, 3.97;
n = ≤ 5) and Registry rescue/recovery workers (SIR = 1.35, 95% CI: 0.70, 2.36;
n = 12); however, confidence intervals were wide [
55,
60]. An earlier study of Registry rescue/recovery workers followed through until 2008 found significant excess multiple myeloma risk (SIR = 2.85, 95% CI: 1.15, 5.88;
n = 7) [
59]. In contrast, there was no evidence of increased risk in the General Responder cohort (SIR = 0.80, 95% CI: 0.41, 1.40;
n = 12) or in Registry registrants not involved in rescue/recovery (SIR = 0.67, 95% CI: 0.31, 1.28;
n = 9) [
58,
60]. In all studies, case numbers were small, adding to estimate uncertainty.
Overall, there is evidence of modestly increased cancer risk in the WTC population. The evidence is strongest for all cancers combined and cancer of the thyroid and prostate; however, there were also intermittent indications of other excess cancers, such as bladder cancer, malignant melanoma, multiple myeloma, leukemia, and non-Hodgkin lymphoma. There are notable limitations. First, the observation period is relatively short given complex tumorigenesis that is expected to occur over decades. Continued follow-up is needed to further elucidate cancer risks. Second, errors in within-study comparisons may result from differences in medical monitoring between groups. For example, the observed increased rates of thyroid cancer, a disease with few known risk factors and none seemingly connected to WTC exposure, may be caused by heightened medical surveillance rather than exposure-related disease [
73]. Yet others argue against a surveillance bias in thyroid cancer findings [
68,
69]. Additional research accounting for potential biases is needed. Third, between-study comparisons merit caution given overlap between cohorts. Future studies pooling data from the three cohorts may help address the overlap and increase statistical power [
77]. Additional molecular studies focusing on mechanisms may inform etiology, pathophysiology, and ultimately aid clinical management. For example, further exploration of
mdig expression may result in its use as a prognostic marker to guide multiple myeloma treatments [
74].